Targeting mTORC1/2 Complexes Inhibit Tumorigenesis and Enhance Sensitivity to 5-Flourouracil (5-FU) in Hepatocellular Carcinoma: A Preclinical Study of mTORC1/2-Targeted Therapy in Hepatocellular Carcinoma (HCC).

摘要: BACKGROUND Although 5-Flourouracil(5-FU) is used as the first-choice treatment for advanced hepatocellular carcinoma (HCC), it associated with acquired and intrinsic resistance. Hyperactivation of mTOR signaling has been linked to tumorigenesis chemoresistance in HCC. The aim this study was evaluate compare antitumor effects mTORC1 inhibitor everolimus mTORC1/2 AZD8055 examine interaction between 5-FU MATERIAL AND METHODS Using cultured HCC cells mouse xenograft, were analyzed mono- combination therapy 5-Flourouracil. RESULTS TSC2-deficient cell lines more sensitive AZD8055. AZD8055, but not everolimus, potently prevented from transitioning G1 phase S TSC2-high-expressing cells. reduced phosphorylation both mTORC2 substrates. In contrast, substrates, increased AKT. Notably, synergistically enhanced efficacy via reversing 5-FU-induced upregulation P-glycoprotein (P-gp). synergistic effect also observed a xenograft model. CONCLUSIONS TSC2 promising efficacy-predicting biomarker inhibitor. showed stronger activity than Moreover, appears be option patients refractory chemotherapy.